Immunoglobulin therapy

Immunoglobulin therapy is used in a variety of conditions, many of which involve decreased or abolished antibody production capabilities, which range from a complete absence of multiple types of antibodies, to IgG subclass deficiencies (usually involving IgG2 or IgG3), to other disorders in which antibodies are within a normal quantitative range, but lacking in quality – unable to respond to antigens as they normally should – resulting in an increased rate or increased severity of infections. In these situations, immunoglobulin infusions confer passive resistance to infection on their recipients by increasing the quantity/quality of IgG they possess. Immunoglobulin therapy is also used for a number of other conditions, including in many autoimmune disorders such as dermatomyositis in an attempt to decrease the severity of symptoms. Immunoglobulin therapy is also used in some treatment protocols for secondary immunodeficiencies such as human immunodeficiency virus (HIV), some autoimmune disorders (such as immune thrombocytopenia and Kawasaki disease), some neurological diseases (multifocal motor neuropathy, stiff person syndrome, multiple sclerosis and myasthenia gravis) some acute infections and some complications of organ transplantation. Immunoglobulin therapy is especially useful in some acute infection cases such as pediatric HIV infection and is also considered the standard of treatment for some autoimmune disorders such as Guillain–Barré syndrome. The high demand which coupled with the difficulty of producing immunoglobulin in large quantities has resulted in increasing global shortages, usage limitations and rationing of immunoglobulin. Australia The Australian Red Cross Blood Service developed their own guidelines for the appropriate use of immunoglobulin therapy in 1997. Immunoglobulin is funded under the National Blood Supply and indications are classified as either an established or emerging therapeutic role or conditions for which immunoglobulin use is in exceptional circumstances only. Subcutaneous immunoglobulin access programs have been developed to facilitate hospital based programs. Human normal immunoglobulin (human immunoglobulin G) (Cutaquig) was approved for medical use in Australia in May 2021. Canada The National Advisory Committee on Blood and Blood Products of Canada (NAC) and Canadian Blood Services have also developed their own separate set of guidelines for the appropriate use of immunoglobulin therapy, which strongly support the use of immunoglobulin therapy in primary immunodeficiencies and some complications of HIV, while remaining silent on the issues of sepsis, multiple sclerosis, and chronic fatigue syndrome. European Union Brands include HyQvia (human normal immunoglobulin), Privigen (human normal immunoglobulin (IVIg)), Hizentra (human normal immunoglobulin (SCIg)), and Flebogamma DIF (human normal immunoglobulin). It is used to treat the following conditions: • primary immunodeficiency syndromes (PID, when people are born with an inability to produce enough antibodies); • hypogammaglobulinaemia (low levels of antibodies) and recurrent bacterial infections in patients with chronic lymphocytic leukaemia (a cancer of a type of white blood cell), in whom prophylactic antibiotics have failed; Deqsiga was authorized for medical use in the European Union in May 2025. United Kingdom The United Kingdom's National Health Service recommends the routine use of immunoglobulin for a variety of conditions including primary immunodeficiencies and a number of other conditions, but recommends against the use of immunoglobulin in sepsis (unless a specific toxin has been identified), multiple sclerosis, neonatal sepsis, and pediatric HIV/AIDS. United States The American Academy of Allergy, Asthma, and Immunology supports the use of immunoglobulin for primary immunodeficiencies, while noting that such usage actually accounts for a minority of usage and acknowledging that immunoglobulin supplementation can be appropriately used for a number of other conditions, including neonatal sepsis (citing a sixfold decrease in mortality), considered in cases of HIV (including pediatric HIV), considered as a second line treatment in relapsing-remitting multiple sclerosis, but recommending against its use in such conditions as chronic fatigue syndrome, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) until further evidence to support its use is found (though noting that it may be useful in PANDAS patients with an autoimmune component), cystic fibrosis, and a number of other conditions. • Anthrasil (anthrax immune globulin- human liquid) • Asceniv (immune globulin intravenous, human-slra) • Bivigam (immune globulin intravenous – human 10% liquid) • Gammagard Liquid (immune globulin infusion- human injection, solution • Gammagard Liquid ERC • Gammagard S/D (immune globulin intravenous- human kit • Gamunex-C, (immune globulin injection human) • Hizentra (immune globulin subcutaneous human) • Hyqvia (immune globulin 10 percent – human with recombinant human hyaluronidase) • Octagam (immune globulin intravenous, human) • Panzyga (immune globulin intravenous, human–ifas) • Qivigy (immune globulin intravenous, human-kthm) • Xembify (immune globulin subcutaneous, human – klhw) • Yimmugo (immune globulin intravenous, human-dira) == Side effects ==

Although immunoglobulin is frequently used for long periods of time and is generally considered safe, immunoglobulin therapy can have severe adverse effects, both localized and systemic. Subcutaneous administration of immunoglobulin is associated with a lower risk of both systemic and localized risk when compared to intravenous administration (hyaluronidase-assisted subcutaneous administration is associated with a greater frequency of adverse effects than traditional subcutaneous administration but still a lower frequency of adverse effects when compared to intravenous administration). Patients who are receiving immunoglobulin and experience adverse events are sometimes recommended to take acetaminophen and diphenhydramine before their infusions to reduce the rate of adverse effects. Additional premedication may be required in some instances (especially when first getting accustomed to a new dosage), prednisone or another oral steroid. Local side effects of immunoglobulin infusions most frequently include an injection site reaction (reddening of the skin around the injection site), itching, rash, and hives. Less serious systemic side effects to immunoglobulin infusions include an increased heart rate, hyper or hypotension, an increased body temperature, diarrhea, nausea, abdominal pain, vomiting, arthralgia or myalgia, dizziness, headache, fatigue, fever, and pain. and adults include chest discomfort or pain, myocardial infarction, tachycardia, hyponatremia, hemolysis, hemolytic anemia, thrombosis, hepatitis, anaphylaxis, backache, aseptic meningitis, acute kidney injury, hypokalemic nephropathy, pulmonary embolism, and transfusion related acute lung injury. IVIG has long been known to induce a decrease in peripheral blood neutrophil count, or neutropenia in neonates, and in patients with Idiopathic Thrombocytopenic Purpura, resolving spontaneously and without complications within 48 h. Possible pathomechanisms include apoptosis/cell death due to antineutrophil antibodies with or without neutrophil migration into a storage pool outside the blood circulation. Immunoglobulin therapy interferes with the ability of the body to produce a normal immune response to an attenuated live-virus vaccine (like MMR) for up to a year, ==Routes of administration==

1950s – intramuscular After immunoglobulin therapy's discovery in 1952, weekly intramuscular injections of immunoglobulin (IMIg) were the norm until intravenous formulations (IVIg) began to be introduced in the 1980s. but for many years subcutaneous administration was considered to be a secondary choice, only to be considered when peripheral venous access was no longer possible or tolerable. A number of other brand names of subcutaneous immunoglobulin have since been approved, although some small-scale studies have indicated that a particular cohort of patients with common variable immunodeficiency (CVID) may develop intolerable side effects with subcutaneous immunoglobulin (SCIg) that they do not with intravenous immunoglobulin (IVIg). == Mechanism of action ==

The precise mechanism by which immunoglobulin therapy suppresses harmful inflammation is likely multifactorial. For example, it has been reported that immunoglobulin therapy can block Fas-mediated cell death. Perhaps a more popular theory is that the immunosuppressive effects of immunoglobulin therapy are mediated through IgG's Fc glycosylation. By binding to receptors on antigen presenting cells, IVIG can increase the expression of the inhibitory Fc receptor, FcgRIIB, and shorten the half-life of auto-reactive antibodies. The ability of immunoglobulin therapy to suppress pathogenic immune responses by this mechanism is dependent on the presence of a sialylated glycan at position CH2-84.4 of IgG. Sialylated-Fc-dependent mechanism was not reproduced in other experimental models suggesting that this mechanism is functional under a particular disease or experimental settings. On the other hand, several other mechanisms of action and the actual primary targets of immunoglobulin therapy have been reported. In particular, F(ab')2-dependent action of immunoglobulin to inhibit activation of human dendritic cells, induction of autophagy, induction of COX-2-dependent PGE-2 in human dendritic cells leading to expansion of regulatory T cells, inhibition of pathogenic Th17 responses, and induction of human basophil activation and IL-4 induction via anti-IgE autoantibodies. Some believe that immunoglobulin therapy may work via a multi-step model where the injected immunoglobulin first forms a type of immune complex in the patient. Once these immune complexes are formed, they can interact with Fc receptors on dendritic cells, which then mediate anti-inflammatory effects helping to reduce the severity of the autoimmune disease or inflammatory state. Other proposed mechanisms include the possibility that donor antibodies may bind directly with the abnormal host antibodies, stimulating their removal; the possibility that IgG stimulates the host's complement system, leading to enhanced removal of all antibodies, including the harmful ones; and the ability of immunoglobulin to block the antibody receptors on immune cells (macrophages), leading to decreased damage by these cells, or regulation of macrophage phagocytosis. Indeed, it is becoming more clear that immunoglobulin can bind to a number of membrane receptors on T cells, B cells, and monocytes that are pertinent to autoreactivity and induction of tolerance to self. A report stated that immunoglobulin application to activated T cells leads to their decreased ability to engage microglia. As a result of immunoglobulin treatment of T cells, the findings showed reduced levels of tumor necrosis factor-alpha and interleukin-10 in T cell-microglia co-culture. The results add to the understanding of how immunoglobulin may affect inflammation of the central nervous system in autoimmune inflammatory diseases. ==Hyperimmune globulin==

Hyperimmune globulins are a class of immunoglobulins prepared in a similar way as for normal human immunoglobulin, except that the donor has high titers of antibody against a specific organism or antigen in their plasma. Some agents against which hyperimmune globulins are available include hepatitis B, rabies, tetanus toxin, varicella-zoster, etc. Administration of hyperimmune globulin provides "passive" immunity to the patient against an agent. This is in contrast to vaccines that provide "active" immunity. However, vaccines take much longer to achieve that purpose while hyperimmune globulin provides instant "passive" short-lived immunity. Hyperimmune globulin may have serious side effects, thus usage is taken very seriously. Hyperimmune serum and plasma contain high amounts of an antibody, as a consequence of disease convalescence or of repeated immunization. Hyperimmune plasma is used in veterinary medicine, and hyperimmune plasma derivatives are used to treat snakebite. It has been hypothesized that hyperimmune serum may be an effective therapy for persons infected with the Ebola virus. ==Society and culture==

Economics In the United Kingdom a dose cost the NHS between GBP|11.20 and 1,200.00 depending on the type and amount. Brand names of intravenous immunoglobulin formulations include Flebogamma, Gamunex, Privigen, Octagam, and Gammagard, while brand names of subcutaneous formulations include Cutaquig, Cuvitru, HyQvia, Hizentra, Gamunex-C, and Gammaked. Supply issues The United States is one of a handful of countries that allow plasma donors to be paid, meaning that the US supplies much of the plasma-derived medicinal products (including immunoglobulin) used across the world, including more than 50% of the European Union's supply. In Australia, blood donation is voluntary and therefore to cope with increasing demand and to reduce the shortages of locally produced immunoglobulin, several programs have been undertaken including adopting plasma for first time blood donors, better processes for donation, plasma donor centres and encouraging current blood donors to consider plasma only donation. ==Research==

Experimental results from a small clinical trial in humans suggested protection against the progression of Alzheimer's disease, but no such benefit was found in a subsequent phase III clinical trial. In May 2020, the US approved a phase three clinical trial on the efficacy and safety of high-concentration intravenous immune globulin therapy in severe COVID-19. Efficacy of heterologous immunoglobulin derivatives has been demonstrated in clinical trials of antivenoms for scorpion sting and for snakebite. == References ==